scholarly journals Aberrant Hepatic Methionine Metabolism and Gene Methylation in the Pathogenesis and Treatment of Alcoholic Steatohepatitis

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Charles H. Halsted ◽  
Valentina Medici
Keyword(s):  
Animal Models ◽  
Liver Injury ◽  
Clinical Data ◽  
Epigenetic Regulation ◽  
Methionine Metabolism ◽  
Cell Models ◽  
Gene Methylation ◽  
Alcoholic Steatohepatitis ◽  
Methionine Cycle

The pathogenesis of alcoholic steatohepatitis (ASH) involves ethanol-induced aberrations in hepatic methionine metabolism that decrease levels of S-adenosylmethionine (SAM), a compound which regulates the synthesis of the antioxidant glutathione and is the principal methyl donor in the epigenetic regulation of genes relevant to liver injury. The present paper describes the effects of ethanol on the hepatic methionine cycle, followed by evidence for the central role of reduced SAM in the pathogenesis of ASH according to clinical data and experiments in ethanol-fed animals and in cell models. The efficacy of supplemental SAM in the prevention of ASH in animal models and in the clinical treatment of ASH will be discussed.

scholarly journals Activation of MAT2A-RIP1 signaling axis reprograms monocytes in gastric cancer

2021 ◽  
Vol 9 (2) ◽  
pp. e001364
Author(s):  
Yan Zhang ◽  
Hui Yang ◽  
Jun Zhao ◽  
Ping Wan ◽  
Ye Hu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Metabolism ◽  
Vital Role ◽  
Methionine Metabolism ◽  
Promoter Regions ◽  
Normal Tissues ◽  
Methionine Cycle

BackgroundThe activation of tumor-associated macrophages (TAMs) facilitates the progression of gastric cancer (GC). Cell metabolism reprogramming has been shown to play a vital role in the polarization of TAMs. However, the role of methionine metabolism in function of TAMs remains to be explored.MethodsMonocytes/macrophages were isolated from peripheral blood, tumor tissues or normal tissues from healthy donors or patients with GC. The role of methionine metabolism in the activation of TAMs was evaluated with both in vivo analyses and in vitro experiments. Pharmacological inhibition of the methionine cycle and modulation of key metabolic genes was employed, where molecular and biological analyses were performed.ResultsTAMs have increased methionine cycle activity that are mainly attributed to elevated methionine adenosyltransferase II alpha (MAT2A) levels. MAT2A modulates the activation and maintenance of the phenotype of TAMs and mediates the upregulation of RIP1 by increasing the histone H3K4 methylation (H3K4me3) at its promoter regions.ConclusionsOur data cast light on a novel mechanism by which methionine metabolism regulates the anti-inflammatory functions of monocytes in GC. MAT2A might be a potential therapeutic target for cancer cells as well as TAMs in GC.

scholarly journals Role of Fn14 in acute alcoholic steatohepatitis in mice

2015 ◽  
Vol 308 (4) ◽  
pp. G325-G334 ◽  
Author(s):  
Gamze Karaca ◽  
Guanhua Xie ◽  
Cynthia Moylan ◽  
Marzena Swiderska-Syn ◽  
Cynthia D. Guy ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Injury ◽  
Control Diet ◽  
Alcohol Exposure ◽  
Tnf Receptor ◽  
High Fat ◽  
Alcoholic Steatohepatitis ◽  
Tnf Α ◽  
Induce Liver Injury

TNF-like weak inducer of apoptosis (TWEAK) is a growth factor for bipotent liver progenitors that express its receptor, fibroblast growth factor-inducible 14 (Fn14), a TNF receptor superfamily member. Accumulation of Fn14+ progenitors occurs in severe acute alcoholic steatohepatitis (ASH) and correlates with acute mortality. In patients with severe ASH, inhibition of TNF-α increases acute mortality. The aim of this study was to determine whether deletion of Fn14 improves the outcome of liver injury in alcohol-consuming mice. Wild-type (WT) and Fn14 knockout (KO) mice were fed control high-fat Lieber deCarli diet or high-fat Lieber deCarli diet with 2% alcohol (ETOH) and injected intraperitoneally with CCl4 for 2 wk to induce liver injury. Mice were euthanized 3 or 10 days after CCl4 treatment. Survival was assessed. Liver tissues were analyzed for cell death, inflammation, proliferation, progenitor accumulation, and fibrosis by quantitative RT-PCR, immunoblot, hydroxyproline content, and quantitative immunohistochemistry. During liver injury, Fn14 expression, apoptosis, inflammation, hepatocyte replication, progenitor and myofibroblast accumulation, and fibrosis increased in WT mice fed either diet. Mice fed either diet expressed similar TWEAK/Fn14 levels, but ETOH-fed mice had higher TNF-α expression. The ETOH-fed group developed more apoptosis, inflammation, fibrosis, and regenerative responses. Fn14 deletion did not reduce hepatic TNF-α expression but improved all injury parameters in mice fed the control diet. In ETOH-fed mice, Fn14 deletion inhibited TNF-α induction and increased acute mortality, despite improvement in liver injury. Fn14 mediates wound-healing responses that are necessary to survive acute liver injury during alcohol exposure.

Role of non-alcoholic steatohepatitis in methotrexate-induced liver injury

2001 ◽  
Vol 16 (12) ◽  
pp. 1395-1401 ◽  
Author(s):  
Gerald Langman ◽  
Pauline De La M Hall ◽  
Gail Todd
Keyword(s):  
Liver Injury ◽  
Alcoholic Steatohepatitis

Role of abnormal methionine metabolism in alcoholic liver injury

Alcohol ◽  
2002 ◽  
Vol 27 (3) ◽  
pp. 155-162 ◽  
Author(s):  
Shelly C Lu ◽  
Hidekazu Tsukamoto ◽  
José M Mato
Keyword(s):  
Liver Injury ◽  
Methionine Metabolism ◽  
Alcoholic Liver Injury

scholarly journals Alternative mechanisms of miR-34a regulation in cancer

2017 ◽  
Vol 8 (10) ◽  
pp. e3100-e3100 ◽  
Author(s):  
Eva Slabáková ◽  
Zoran Culig ◽  
Ján Remšík ◽  
Karel Souček
Keyword(s):  
Cell Proliferation ◽  
Clinical Trials ◽  
Animal Models ◽  
Tumor Suppressor ◽  
Epigenetic Regulation ◽  
Feedback Loops ◽  
Cancer Cell Proliferation ◽  
Resistance To Therapy ◽  
Relevant Context

Abstract MicroRNA miR-34a is recognized as a master regulator of tumor suppression. The strategy of miR-34a replacement has been investigated in clinical trials as the first attempt of miRNA application in cancer treatment. However, emerging outcomes promote the re-evaluation of existing knowledge and urge the need for better understanding the complex biological role of miR-34a. The targets of miR-34a encompass numerous regulators of cancer cell proliferation, survival and resistance to therapy. MiR-34a expression is transcriptionally controlled by p53, a crucial tumor suppressor pathway, often disrupted in cancer. Moreover, miR-34a abundance is fine-tuned by context-dependent feedback loops. The function and effects of exogenously delivered or re-expressed miR-34a on the background of defective p53 therefore remain prominent issues in miR-34a based therapy. In this work, we review p53-independent mechanisms regulating the expression of miR-34a. Aside from molecules directly interacting with MIR34A promoter, processes affecting epigenetic regulation and miRNA maturation are discussed. Multiple mechanisms operate in the context of cancer-associated phenomena, such as aberrant oncogene signaling, EMT or inflammation. Since p53-dependent tumor-suppressive mechanisms are disturbed in a substantial proportion of malignancies, we summarize the effects of miR-34a modulation in cell and animal models in the clinically relevant context of disrupted or insufficient p53 function.

scholarly journals Non-Alcoholic Steatohepatitis: A Review of Its Mechanism, Models and Medical Treatments

2020 ◽  
Vol 11 ◽  
Author(s):  
Cheng Peng ◽  
Alastair G. Stewart ◽  
Owen L. Woodman ◽  
Rebecca H. Ritchie ◽  
Cheng Xue Qin
Keyword(s):  
Animal Models ◽  
Liver Injury ◽  
Liver Steatosis ◽  
The United States ◽  
Diagnostic Tools ◽  
Pharmacological Agents ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Increased Risk ◽  
Metabolic Disruption

Non-alcoholic steatohepatitis (NASH) develops from non-alcoholic fatty liver disease (NAFLD). Currently, around 25% of the population is estimated to have NAFLD, and 25% of NAFLD patients are estimated to have NASH. NASH is typically characterized by liver steatosis inflammation, and fibrosis driven by metabolic disruptions such as obesity, diabetes, and dyslipidemia. NASH patients with significant fibrosis have increased risk of developing cirrhosis and liver failure. Currently, NASH is the second leading cause for liver transplant in the United States. More importantly, the risk of developing hepatocellular carcinoma from NASH has also been highlighted in recent studies. Patients may have NAFLD for years before progressing into NASH. Although the pathogenesis of NASH is not completely understood, the current “multiple-hits” hypothesis suggests that in addition to fat accumulation, elevated oxidative and ER stress may also drive liver inflammation and fibrosis. The development of clinically relevant animal models and pharmacological treatments for NASH have been hampered by the limited understanding of the disease mechanism and a lack of sensitive, non-invasive diagnostic tools. Currently, most pre-clinical animal models are divided into three main groups which includes: genetic models, diet-induced, and toxin + diet-induced animal models. Although dietary models mimic the natural course of NASH in humans, the models often only induce mild liver injury. Many genetic and toxin + diet-induced models rapidly induce the development of metabolic disruption and serious liver injury, but not without their own shortcomings. This review provides an overview of the “multiple-hits” hypothesis and an evaluation of the currently existing animal models of NASH. This review also provides an update on the available interventions for managing NASH as well as pharmacological agents that are currently undergoing clinical trials for the treatment of NASH.

scholarly journals O-GlcNAcylation regulates the methionine cycle to promote pluripotency of stem cells

2020 ◽  
Vol 117 (14) ◽  
pp. 7755-7763
Author(s):  
Qiang Zhu ◽  
Xuejun Cheng ◽  
Yaxian Cheng ◽  
Junchen Chen ◽  
Huan Xu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Critical Role ◽  
Embryonic Stem ◽  
Methionine Metabolism ◽  
Somatic Cell Reprogramming ◽  
Methionine Cycle ◽  
Induced Pluripotent ◽  
Important Enzyme

Methionine metabolism is critical for the maintenance of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) pluripotency. However, little is known about the regulation of the methionine cycle to sustain ESC pluripotency. Here, we show that adenosylhomocysteinase (AHCY), an important enzyme in the methionine cycle, is critical for the maintenance and differentiation of mouse embryonic stem cells (mESCs). We show that mESCs exhibit high levels of methionine metabolism, whereas decreasing methionine metabolism via depletion of AHCY promotes mESCs to differentiate into the three germ layers. AHCY is posttranslationally modified with an O-linked β-N-acetylglucosamine sugar (O-GlcNAcylation), which is rapidly removed upon differentiation. O-GlcNAcylation of threonine 136 on AHCY increases its activity and is important for the maintenance of trimethylation of histone H3 lysine 4 (H3K4me3) to sustain mESC pluripotency. Blocking glycosylation of AHCY decreases the ratio of S-adenosylmethionine versus S-adenosylhomocysteine (SAM/SAH), reduces the level of H3K4me3, and poises mESC for differentiation. In addition, blocking glycosylation of AHCY reduces somatic cell reprogramming. Thus, our findings reveal a critical role of AHCY and a mechanistic understanding of O-glycosylation in regulating ESC pluripotency and differentiation.

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